An Update on ICH Guideline Q8

– Pharmaceutical Development
FDA Advisory Committee for Pharmaceutical
Science: 5 Oct 2006
Dr John C Berridge
Senior Regulatory Consultant
Pfizer
ISPE Vienna Congress 2006

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Presentation Outline

Background to Q8
Experience of Q8 to date
Implications of Q8
Future strategy for Q8

2
 July 2003: An ICH vision
Our vision: The future Pharmaceutical Quality System

For companies with :

Quality Risk 1. Good design and
The Regulatory Management control strategies
Quality System
(Q9) 2. Good Risk
Quality Risk Management strategies
Management 3. Good Quality Systems

Quality by Design
(Pharmaceutical Quality
Development)
by Design Reduced regulatory
Quality
burden:
Systems (Q8) • Reduction of
submissions on
changes/variations
Existing GMP
GMP’’s Quality • Inspection of quality
Systems systems
(Q10)
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 Q8– an opportunity for change
Traditional Future

Empirical Systematic

Data Driven Knowledge driven

Retrospective Prospective

“Test to document Science and Risk based

quality” Q8 Acceptance criteria
Acceptance criteria based on patient needs
based on limited batch Variability explored and
data understood (Design
Variability not understood Space)
and avoided

4
 On July 20th 2004 you were told Q8
could deliver:-

 Product quality and performance achieved and assured

by design of effective and efficient manufacturing
processes

 Product specifications based on mechanistic

understanding of how formulation and process factors
impact product performance

 An ability to effect Continuous Improvement and

Continuous "real time" assurance of quality

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 The EWG has delivered the core
guideline
Q8 is a 2 part guideline

Part 1 Revision
Core document
Baseline expectations
Optional information
Regulatory Flexibility
Step 4: Nov 2005
Annexes relating to
specific dosage forms
(as Q6a)
References to use of
risk management
Focus on guiding
towards Desired State
Drafting underway

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Presentation Outline

Background to Q8
Experience of Q8 to date
Implications of Q8
Future strategy for Q8

7
 We have recognised Q8 encourages a new
development paradigm – Quality by Design

Product/ Product/
Target
Process Process Control
Product
Dev. Design Strategy
Profile
Space

Define Incorporate Through hypothesis Define control

product prior testing, create strategy based
intended knowledge, scientific on Quality Risk
use & Risk understanding of Mgmt & Design
quality Assessment, product and process. Space leading
targets (wrt DoE and PAT Identify ’critical to to control of
efficacy & to create New quality attributes’ and quality relevant
safety) Scientific establish multi-variate to safety and
Knowledge, ”Design Space” that efficacy.
assures Quality

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 Quality by Design starts with the Patient, delivers
consistently to the patient, but welcomes variability!
..we need to manufacture by a
process that is well understood,
robust, but adaptable…

To provide a product
that consistently … to the variability of
meets their needs….
input materials
-API, Excipients etc
= DESIGN SPACE
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 Design Space: 3 key concepts
Design Space: the multidimensional combination
and interaction of input variables (e.g., material
attributes) and process parameters that have been
demonstrated to provide assurance of quality.
Working within the design space is not considered
as a change. Movement out of the design space is
considered to be a change and would normally
initiate a regulatory post approval change process.
Design space is proposed by the applicant and is
subject to regulatory assessment and approval.

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 Q8 applies throughout product life-cycle

Product Technology Commercial

Development Transfer Manufacture

Design quality product & Demonstration of Risk-based regulatory

process to consistently greater understanding decisions (reviews and
deliver intended of pharmaceutical and inspections);
performance. manufacturing Manufacturing process
sciences can create a improvements, within the
Knowledge gained from basis for flexible approved design space,
without further regulatory
development studies & regulatory approaches. review.
manufacturing experience
Reduction of post-
provide scientific approval submissions
understanding to support
Real-time quality control,
the establishment of the leading to a reduction of
design space, specs, & end-product release
manufacturing controls. testing
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 Industry is capitalising on Q8
NDA/CTD submissions are changing
‘Here is my science, here is my manufacturing
scheme which was developed through my science,
here is how they link together’
– M Kovalycsik - Wyeth
FDA pilot program
Design Space submissions
Continuous process verification
– Compliance policy 7132c.08

Already Q8 is delivering value to the Industry, the Regulators

and, ultimately, the patient
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Presentation Outline

Background to Q8
Experience of Q8 to date
Implications of Q8
Future strategy for Q8

13
 Understanding the full implications of Q8
is not easy
The Q8 EWG believes the core guideline needs exemplifying

What is Quality by Design?

What’s the difference from the way pharmaceutical
development has been approached and described until
now?
Can we help in distinguishing baseline or ‘minimum’ from
enhanced?
How exactly does the applicant describe the Design
Space?

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 Q8 challenge example – What is
Design Space?
60C

2.0 5.0 pH
30C
Traditional Method:
Carry out the reaction at pH 2-5
and between 30 and 60C
= ‘Proven Acceptable Ranges’
How do we describe the <criterion>, relationship and associated control strategy?
Design Space:
Carry out the crystallisation to create
particles at size/shape <criterion> varying
the temperature, stirring rate and super
saturation according to the relationship:
Size = f(temperature) + f(stirring) + f(super
saturation)
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 Wider implications of Q8
development
 Can we clearly articulate what we mean by Quality by Design
and understand its implications for both the Industry and
Regulators?
 As we complete revision of Q8 should we add a glossary of key
terms, perhaps illustrated through examples?
 How should we address API development & manufacture for
both chemical and biotech?
 Draft concept paper for NCE API available
 Biotech paper not endorsed by ICH
– Critical we assess implications of “Quality by Design”
 Q8 is impacting the way we define specifications (Q6A & Q6B)
 There may be other things needing consideration
 E.g. analytical methods

These issues likely to be raised at ICH quality strategy discussion

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Presentation Outline

Background to Q8
Experience of Q8 to date
Implications of Q8
Future strategy for Q8

17
 Progression of Q8
EWG has changed its focus for the revision from
parenterals to solid oral dosage forms
Because it provides the greatest opportunity (lots of
background and expertise) and is most common dosage
form
When oral solids agreed, we will address the other
types of dosage form
Illustrate QbD principles
Examples drawn from EFPIA mock P2 document
Ensure that we are clear on Design Space
Step 2 date hard to predict

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 Progression should continue since Q8 is positively
impacting Industry and Regulatory Practices

Science-based (Quality by Design) approaches will bring needed

medicines to patients in more robust and effective way and unlock
the innovative potential of the industry
Regulators are responding supportively
FDA:
• Development of elite teams comprising investigators, analysts and compliance
officers from field and CDER organisations : capable of making judgements about a
firm’s risk management programmes, product and process knowledge, process
capability and robustness of quality systems.
• Considering making revisions to its post-approval change reporting regulations (21
CFR 314.70) to accommodate more "regulatory flexibility" for drug makers operating
within their pre-disclosed design space
– J Clark 28-8-06
EMEA: Revision of Variations Regulations
• “We have come to the conclusion that the concepts laid down in these guidelines –
also taking into account the ongoing work of Q10 – could not be properly
implemented in the EU without amendments to the Variations Regulations”
G Lalis, EC; 16-3-06

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 Ultimately, it’s all about structured
KNOWLEDGE: this links with Q10

Comm Knowledge
Production

Tech
Transfer

Clin Dev

TPP Prod/Proc Design Control

Development Space Strategy
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 Q8, Q9, Q10 – the opportunity
Our vision: The future Pharmaceutical Quality System

To deliver the Quality Risk

For companies with :
1. Good design and

ICH Vision and

The Regulatory Management control strategies
Quality System
(Q9) 2. Good Risk
Quality Risk Management strategies
Management 3. Good Quality Systems

modernize Quality
Systems
Quality by Design
(Pharmaceutical
Development)
Quality
by Design
(Q8)
Reduced regulatory
burden:

Pharmaceutical
• Reduction of
submissions on
changes/variations
Existing GMP
GMP’’s Quality • Inspection of quality
Systems systems

Manufacturing (Q10)

and associated
regulatory BOTH Industry and Regulators need
to work together to change the current
processes………. paradigm and mindsets……..
– Q8 / Q9 / Q10 providing a ‘once
in a lifetime’ opportunity
– Let us progress the concepts
and guidelines with enthusiasm
and optimism!
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